Psychiatric diseases and disorders include, but are not limited to, schizophrenia, schizophreniform disorders, schizoaffective disorders, bipolar disorders (such as bipolar disorders type I, bipolar disorders type II, mania, hypomania), non-bipolar mania, Tourette's syndrome, cyclothymic disorders, rapid cycling, ultradian cycling, personality disorders, attention disorders with or without hyperactive behaviour, delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorders due to a general medical condition, psychotic disorders associated to Parkinson's disease, substance-induced psychotic disorders or a psychotic disorders not otherwise specified, anxiety disorders such as generalised anxiety disorders, panic disorders, post-traumatic stress disorders, impulse control disorders, phobic disorders and dissociative states.
Schizophrenia and related disorders (brief psychotic disorders, delusional disorders, schizoaffective disorders, and schizophreniform disorders) are among the most severe and debilitating forms of psychiatric disorders. As used hereinafter in this description and claims the term “schizophrenia” includes schizophrenia related disorders such as brief psychotic disorders, delusional disorders, schizoaffective disorders, and schizophreniform disorders.
Schizophrenia is characterized by profound disruption of the most fundamental human attributes: language, thought, perception, affect, and sense of self. The array of symptoms frequently includes psychotic manifestations such as hearing internal voices or experiencing other sensations not connected to an obvious source (hallucinations), assigning unusual significance or meaning to normal events (paranoia) or holding fixed false personal beliefs (delusions) and loss of contact with reality. No single symptom is definitive for diagnosis; rather, the diagnosis encompasses a pattern of signs and symptoms, in conjunction with impaired occupational or social functioning.
Generally, symptoms of schizophrenia are categorized as positive, disorganized, negative and cognitive. Positive symptoms are characterized by an excess or distortion of normal functions; negative symptoms, by diminution or loss of normal functions. Disorganized symptoms include thought disorders and bizarre behaviour. Cognitive symptoms are deficits in information processing and problem solving. A person may have symptoms from one or all categories.
However, traditional treatments for schizophrenia are not very effective to treat cognitive deficits in schizophrenia. While it has been reported that more recently developed treatments for schizophrenia, known as “atypical anti-psychotics,” may have some effect on cognitive deficits, the effect may not be lasting or not lead to an improvement in daily functioning. In fact there has been little data demonstrating the efficacy of atypical antipsychotics, the most common treatment prescribed for schizophrenia, in the treatment of cognitive impairment, wile psychosocial and cognitive behavioural therapy is still forming the basis of treatment.
On the other hand, disturbance in cognition can be associated with a variety of diseases (e.g., schizophrenia, obsessive compulsive disorders, psychosis, bipolar disorders, anxiety, depression, attention deficit hyperactivity disorder, autism, dyslexia, Tourette's syndrome, Mild Cognitive Impairment (MCI) and disorders of learning in children, adolescents and adults, Age Associated Memory Impairment, Age Associated Cognitive Decline, Alzheimer's Disease, Down's Syndrome, traumatic brain injury, Huntington's Disease, Progressive Supranuclear Palsy (PSP), HIV, stroke, vascular diseases, Pick's or Creutzfeldt-Jacob diseases, multiple sclerosis (MS) and other white matter disorders, Parkinson's Disease) but cannot be identified with the disease itself. However, it is evident for the person skilled in the art that it is essential to distinguish between curing or alleviating a specific symptom, that can be common to a variety of different diseases, and to treat the disease itself.
Different hypotheses have been proposed to try to explain the aetiology of schizophrenia. Various neurotransmitter systems seem to be implicated in the pathology: hyperactivity of the dopaminergic circuits (Baumeister A A, Francis J L, J. Hist. Neurosci.; 2002 September; 11(3): 265-77), imbalance of the gabaergic system (Squires R F, Saederup E, Neurochem. Res., 1991 October; 16(10): 1099-111), NMDA receptor hypo-function state, as well as an impairment of the cholinergic function (Woodruff-Pak D S, Gould T J. Behav. Cogn. Neurosci. Rev. 2002 March; 1(1): 5-20).
Despite major research achievements, the underlying pathophysiology of schizophrenia, including molecular causes and mechanisms, is currently rather incomplete and, in spite of progress in medication of schizophrenia, there are still patients who are resistant to treatments with neuroleptics and mood stabilizers and the unmet medical need is high.
By the late 1970s, it was already clear that the key pharmacological action of antipsychotic drugs was their ability to block dopaminergic D2 receptors, specifically in the mesolimbic dopamine pathway, in that reducing the hyperactivity in this area that is postulated to cause the positive symptoms of psychosis. Unfortunately it is not possible to block dopaminergic overactivity in that specific area only, thus conventional antipsychotics have severe side effects due to the block of D2 receptors in other areas, such as the nigrostriatal pathway, responsible for the control of movements. More recent compounds, such as atypical antipsychotics, have serotonin receptor antagonism on top of D2 receptor antagonism: these characteristics lead to a better disease control with fewer side effects. On the other hand, even if a decrease in dopaminergic tone is considered essential for antipsychotic activity, the modulation of glutamatergic transmission may be equally important. In support to this hypothesis is the fact that symptoms similar to schizophrenia can be induced in healthy volunteers by NMDA antagonists. For decades it has been recognized that the potent NMDA antagonist, phencyclidine (PCP) produces psychotic symptoms in abusers that are remarkably similar to schizophrenia. See Morgan C J et al., Neuropsychopharmacology. 2004 January; 29(1): 208-18; Large C H, J. Psychopharmacol.; 2007 May; 21(3): 283-301.
This data suggests that hypofunction of NMDA receptors might be involved in the generation of negative symptoms of the disease. See also Mouri A et al., Neurochem. Int.; 2007 July-September; 51(2-4): 173-84; Lindsley C W et al., Curr. Top. Med. Chem. 2006; 6(8): 771-85; Thornberg S A, and Saklad S R, Pharmacotherapy.; 1996 January-February; 16(1): 82-93; Javitt D C. Int. Rev. Neurobiol.; 2007 78:69-108.
Patients with schizophrenia, Tourette's syndrome, panic disorders, and obsessive compulsive disorders, exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition of startle (PPI). See Geyer, Dial. Clin. Neurosci.; 2006 8(1): 9-16; Geyer et al., Psycopharmacology; 2001 July; 156(2-3): 117-54. The reduced ability to filter out among irrelevant auditory stimulation is a characteristic thought to contribute to certain manifestations of these conditions including inattention, distractibility, and cognitive deficits. Similar deficits in PPI are produced in rats by different pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face and predictive validity. In rodents, disruptions in PPI of startle can be produced by: stimulation of dopaminergic (DA) receptors, induced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors, and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Typical and atypical antipsychotics, mood stabilizers, AChE inhibitors and nicotine are effective in restoring PPI disruption induced by the different manipulations.
Anxiety and anxiety related disorders, as specified hereinbelow, cover several different forms of abnormal, pathological anxiety, fears and phobias. Each anxiety related disorder has different symptoms, but all the symptoms cluster around excessive, irrational fear and dread. Anxiety related disorders include panic disorders, obsessive-compulsive disorders (OCD), post-traumatic stress disorders (PTSD), social phobia (or social anxiety disorders), specific phobias, and generalized anxiety disorders (GAD).
The principal medications used for anxiety and anxiety related disorders range from anti-anxiety drugs (benzodiazepines and barbiturates), antidepressants to beta-blockers and have different mechanisms of action. However in some cases there is no correspondence between the therapeutical treatment of the disease and the effect on some of the symptoms which may be associated herewith. For instance, with regard to anxiety related cognition impairments, the results of different studies demonstrate instead that the reduction in anxiety shown by anxious patients after diazepam is not accompanied by a reduction in cognitive disorders. This suggests that diazepam fails to reduce anxiety-related cognitive impairments in clinically anxious subjects. See Cognitive Therapy and Research 1991, 15(6):459-467.
Among the different classes of drugs currently used for the psychiatric disorders above described, many side effects can be observed and therefore a high unmet medical need is perceived for these pathologies. For instance, lithium salts have a narrow therapeutic index; atypical antipsychotics can cause an increased QTc interval and/or weight gain; anticonvulsants cause sedation and cognitive impairments and antidepressants can cause a swing towards mania. Although the side effect profile of each individual drug differs significantly, it is clear that the side-effect profiles of these drugs are far from desirable. Moreover, there are frequently comorbid psychiatric conditions that are also of clinical importance.
Although epidemiological studies report a high prevalence of anxiety and anxiety related disorders in schizophrenia, their clinical relevance is still under recognized. The presence of anxiety in schizophrenia patients has been associated with a greater risk of suicide, poorer social functioning, and an increase risk of relapse. Bayle et al. (Eur Psychiatry 2001; 16-349-353) reported that 47.5% of schizophrenia patients had a lifetime history of panic attacks, that in 31.2% of cases the onset of panic disorder preceded the onset of schizophrenia, and that the treatment of panic disorder improved clinical and social outcome.
While comorbid panic and obsessive-compulsive disorder have been investigated in schizophrenia patients, social anxiety in schizophrenia has received much less clinical attention. People with social anxiety suffer considerable impairments in daily life activities, occupational role, and social relationship. Social anxiety is itself a disabling disorder and individuals with social anxiety disorders as comorbid conditions have a more severe level of disability. Subjects with social anxiety have a higher risk of developing substance/alcohol abuse or dependence and in patients with schizophrenia this is associated to a higher impulsivity and suicidality. Therefore the assessment and treatment of social anxiety disorder comorbidity in schizophrenia patients should improve both clinical and social outcomes. See Pallanti S. et al.—Am J Psychiatry (2004) 161:53-58.
By way of further background, WO90/14334 discloses substituted alpha-aminoamide derivatives active on the central nervous system (CNS) that are useful in the treatment of epilepsy, of Parkinson's disease and as neuroprotective agents in degenerative processes associated with normal ageing or pathological situations, such as brain ischemia; they can also be used as antidepressants, hypnotics and/or antispastic agents. See also Pevarello P. et al. (1998), “Synthesis and anticonvulsant activity of a new class of 2-[(arylalkyl)amino]alkanamide derivatives”, J. Med. Chemistry, 41: 579-590.
WO99/26614 discloses substituted alpha-aminoamide derivatives active for the treatment of neuronal damage following global and focal ischemia, for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and for treatment, prevention or amelioration of pain, as anticonvulsant, and as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy.
WO07/071,311 discloses 2-phenylethylamino derivatives active as calcium and/or sodium channel modulators and therefore useful in preventing alleviating and curing neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, urogenital, and gastrointestinal diseases where the above mechanisms have been described as playing a pathological role.
EP 1870097 A, published on 26 Dec. 2007 and corresponding to WO 2007/144153, published on 21 Dec. 2007, discloses α-aminoamide derivatives for the treatment of cognitive impairment symptoms associated to a variety of neuropsychiatric disorders such as schizophrenia, obsessive compulsive disorders, psychosis, bipolar disorders, anxiety, depression, attention deficit hyperactivity disorder, autism, dyslexia, Tourette's syndrome, Mild Cognitive Impairment (MCI) and disorders of learning in children, adolescents and adults, Age Associated Memory Impairment, Age Associated Cognitive Decline, Alzheimer's Disease, Down's Syndrome, traumatic brain injury, Huntington's Disease, Progressive Supranuclear Palsy (PSP), HIV, stroke, vascular diseases, Pick's or Creutzfeldt-Jacob diseases, multiple sclerosis (MS) and other white matter disorders, Parkinson's Disease.